2. Academic Validation
  3. Adolescent co-exposure to environmental cadmium and high-fat diet induces cognitive decline via Larp7 m6A-mediated SIRT6 inhibition

Adolescent co-exposure to environmental cadmium and high-fat diet induces cognitive decline via Larp7 m6A-mediated SIRT6 inhibition

  • J Hazard Mater. 2024 Jul 8:476:135159. doi: 10.1016/j.jhazmat.2024.135159.
Jin Zhang 1,  Yong-Wei Xiong 2,  Hua-Long Zhu 2,  Lu-Lu Tan 1,  Huan Zhou 1,  Xin-Mei Zheng 1,  Yu-Feng Zhang 1,  Wei Chang 1,  De-Xiang Xu 2,  Tian Wei 3,  Su-Zhen Guan 4,  Hua Wang 5
Affiliations

Affiliations

  • 1 Department of Toxicology, School of Public Health, Center for Big Data and Population Health of IHM, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
  • 2 Department of Toxicology, School of Public Health, Center for Big Data and Population Health of IHM, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, China.
  • 3 Department of Toxicology, School of Public Health, Center for Big Data and Population Health of IHM, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, China. Electronic address: weitfield@126.com.
  • 4 School of Public Health, Ningxia Medical University, China. Electronic address: guansz_nx2017@sina.com.
  • 5 Department of Toxicology, School of Public Health, Center for Big Data and Population Health of IHM, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, China. Electronic address: wanghuadev@ahmu.edu.cn.
PMID: 39002485 DOI: 10.1016/j.jhazmat.2024.135159
Abstract

The effects and underlying mechanisms of adolescent exposure to combined environmental hazards on cognitive function remain unclear. Here, using a combined exposure model, we found significant cognitive decline, hippocampal neuronal damage, and neuronal senescence in mice exposed to cadmium (Cd) and high-fat diet (HFD) during adolescence. Furthermore, we observed a significant downregulation of Sirtuin 6 (SIRT6) expression in the hippocampi of co-exposed mice. UBCS039, a specific SIRT6 Activator, markedly reversed the above adverse effects. Further investigation revealed that co-exposure obviously reduced the levels of La ribonucleoprotein 7 (LARP7), disrupted the interaction between LARP7 and SIRT6, ultimately decreasing SIRT6 expression in mouse hippocampal neuronal cells. Overexpression of Larp7 reversed the combined exposure-induced SIRT6 decrease and senescence in mouse hippocampal neuronal cells. Additionally, the results showed notably elevated levels of Larp7 m6A and YTH domain family protein 2 (YTHDF2) in mouse hippocampal neuronal cells treated with the combined hazards. Ythdf2 short interfering RNA, RNA immunoprecipitation, and RNA stability assays further demonstrated that YTHDF2 mediated the degradation of Larp7 mRNA under combined exposure. Collectively, adolescent co-exposure to Cd and HFD causes hippocampal senescence and cognitive decline in mice by inhibiting LARP7-mediated SIRT6 expression in an m6A-dependent manner.

Keywords

Cadmium; Cognitive function; High-fat diet; LARP7; SIRT6.

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